The OD’s role with new diabetes drugs

Ever since the oral diabetes medication rosiglitazone (Avandia, GlaxoSmithKline) was found to increase the risk of congestive heart failure by several analyses after U.S. Food and Drug Administration (FDA) approval, the FDA has required all new diabetes medications to not only demonstrate clinically meaningful reductions in blood glucose but also undergo more rigorous cardiovascular (CV) outcomes safety trials.¹

Consequently, a number of new agents have been found to decrease the risk of mortality in general and CV mortality in particular.² A reduction in major adverse cardiovascular events (MACE), including heart attack, stroke and hospitalization for congestive heart failure (CHF), has also accompanied the introduction of some medications per recent findings.³

Previously from Dr. Chous: New strategies to assess the risk of diabetes-related vision loss

It is important for eyecare providers to be familiar with these new drugs and findings. We often see patients with diabetes, metabolic syndrome, and high CV risk, and we are in a position to help counsel our patients about new treatments-and even suggest that appropriate patients have conversations with their primary-care physicians, endocrinologists and cardiologists.

GLP-1 analogs

Glucagon-like peptide-1 (GLP-1) analogs are drugs that mimic the action of their namesake gut-derived protein secreted when food passes through the terminal ileum of the small intestine. GLP-1 has multiple effects on blood glucose, causing a short-term release of endogenous insulin from functioning pancreatic beta cells as well as suppressing glucagon by pancreatic alpha cells and appetite by affecting hypothalamic satiety receptors.⁴

Evidence shows that GLP-1 production is lost in type 2 diabetes and that injectable GLP-1 analogs like exenatide (Byetta and Bydureon, AstraZeneca), liraglutide (Victoza, Novo Nordisk), and dulaglutide (Trulicity, Lilly) lower glycosylated hemoglobin and assist with weight loss.⁵

Related: How diabetes is linked to gut bacteria

The LEADER Trial showed that adding liraglutide reduced the risk of MACE and cardiovascular mortality by 13 percent and 22 percent, respectively, compared to standard care.⁶ Though retinopathy rates were not significantly different, the risk of diabetic nephropathy was reduced by 22 percent in the liraglutide treatment arm.

Of interest, an extended release GLP-1 analog (semiglutide) awaiting FDA approval also has been associated with reduced cardiovascular (CV) risk but worsening diabetic retinopathy in patients with poor HbA1c at baseline and who achieved significant reductions in mean blood glucose (> 1.8 point drop in HbA1c). This phenomenon is also seen with insulin therapy and attributed to the so-called “glycemic re-entry effect” rather than the drug molecule itself.^7,8

SGLT2 inhibitors

Sodium glucose transporter-2 reuptake (SGLT2) inhibitors are novel drugs that block normal reabsorption of serum glucose at the proximal renal tubule, allowing increased urinary excretion of glucose and osmotic diuresis.⁹

These drugs decrease blood pressure and arterial stiffness, assist with weight loss, and have shown benefit in early- (but not late-) stage diabetic kidney disease.¹⁰

Three agents are currently available: canagliflozin (Invokana, Janssen), dapagliflozin (Farxiga, AstraZeneca) and empagliflozin (Jardiance, Lilly).

The EMPA-Reg trial conducted in Europe showed a 38 percent reduction in mortality and a 35 percent reduction in hospitalization for congestive heart failure with empagliflozin compared to usual care.¹¹

The CANVASS trial showed similar but less robust results with canagliflozin, but there was an increased risk of lower limb amputation associated with this particular agent.¹²

Recently, use of any SGLT2 drug was associated with reduced risk of mortality in type 2 diabetes patients with established cardiovascular disease (53 percent reduced risk) and without cardiovascular disease (46 percent reduced risk) over an eight-month period in a cohort of more than 150,000 European and American patients.¹³

In addition to effects on blood glucose, SGLT2 receptors have been found in renal mesangial cells and retinal pericytes, suggesting a protective mechanism for SGLT2 inhibitors for both diabetes-related kidney and retinal disease. Plus, dapagliflozin has demonstrated the ability to prevent vascular remodeling in human subjects with diabetes.^14,15

An “old/new” arrival to the diabetes armamentarium is a quick release version of bromocriptine mesylate (Cycloset, Valeant). Bromocriptine (Parlodel, Novartis ) has been used to treat prolactin-secreting pituitary adenomas and growth hormone deficiency for decades. This new iteration briefly suppresses serotonin and upregulates dopamine when taken upon awaking, resulting in reduced sympathetic tone, blood glucose, and triglycerides.

Related: Worldwide diabetes epidemic approaches half a billion

Cardiovascular outcomes trials with Cycloset added to metformin show reduced HbA1c and a 50+ percent reduced risk of heart attack, coronary artery bypass graft, stroke, hospitalization, or death.¹⁶

Case example

T.R. is a 67-year-old male with type 2 diabetes for 15 years. He has previously received multiple coronary artery stents and has congestive heart failure. He has microalbuminuria and peripheral diabetic neuropathy. His last HbA1c was 8.2 percent on metformin, and his in-office blood pressure measured 157/94 mm Hg on lisinopril, metoprolol, and low-dose hydrocholorothiazide. The patient weighs 240 lbs and is 5 feet 8 inches tall.

Dilated fundus exam reveals mild-moderate nonproliferative diabetic retinopathy without macular edema in each eye.

I discussed with the patient exam findings and various treatment options, including ultra-low carbohydrate diet, alternate daily fasting with a goal of reducing HbA1c to less than 7.5 percent, 50 pounds weight loss (per endocrinology) and newer diabetes agents that assist with weight loss and lower CV risk (GLP-1 analogs and SGLT2 inhibitors).

I specifically mentioned the EMPA-Reg trial and suggested the patient discuss this with the endocrinologist and cardiologist and followed up with a letter to both providers.

T.R. returned for an unscheduled visit three weeks later to tell me the cardiologist was “very impressed by your optometrist’s report” and had started T.R. on Jardiance after discussing with endocrinology.

Related: Why the periphery matters in DR progression

At six-month follow-up eye examination, T.R.’s retinopathy is unchanged, his HbA1c is 7.6 percent, his blood pressure is 145/90 mm Hg, and he reports 12 pounds of weight loss.

Costs vs. benefits

These newer diabetes drugs are not inexpensive, and many physicians have told me that insurance company pharmacy benefits managers dictate exactly which drugs are and aren’t feasible options for specific patients.

However, diabetes increases the risk of MACE and CV mortality by two to four times, with hospitalizations accounting for the majority of national diabetes expenditures annually. It may turn out that significantly reduced CV risk with newer, more expensive agents is offset by reduced cost of in-patient care.¹⁷

References

1. Khalaf KI, Taegtmeyer H. After Avandia: The Use of Antidiabetic Drugs in Patients with Heart Failure. Tex Heart Inst J. 2012;39(2):174-178.

2. Rahelić D, Javor E, Lucijanić T, Skelin M. Effects of antidiabetic drugs on the incidence of macrovascular complications and mortality in type 2 diabetes mellitus: a new perspective on sodium-glucose co-transporter 2 inhibitors. Ann Med. 2017 Feb;49(1):51-62.

3. Giugliano D, Maiorino MI, Bellastella G, Esposito K. Type 2 diabetes and cardiovascular prevention: the dogmas disputed. Endocrine. 2017 Sep 11. doi: 10.1007/s12020-017-1418-y. [Epub ahead of print]

4. Pabreja K, Mohd MA, Koole C, Wootten D, Furness SGB. REVIEW Molecular mechanisms underlying physiological and receptor pleiotropic effects mediated by GLP-1R activation. Br J Pharmacol. 2014 Mar;171(5):1114-1128.

5. Samson SL, Garber AJ. A Plethora of GLP-1 Agonists: Decisions About What to Use and When. Curr Diab Rep. 2016 Dec;16(12):120.

6. Álvarez-Villalobos NA, Treviño-Alvarez AM, González-González JG. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2016 Nov 3;375(18):1797-8.

7. Marso SP, Holst AG, Vilsbøll T. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med. 2017 Mar 2;376(9):891-2.

8. Simó R, Hernández C. GLP-1R as a Target for the Treatment of Diabetic Retinopathy: Friend or Foe? Diabetes. 2017 Jun;66(6):1453-1460.

9. Pfister M, Whaley JM, Zhang L, List JF. Inhibition of SGLT2: a novel strategy for treatment of type 2 diabetes mellitus. Clin Pharmacol Ther. 2011 Apr;89(4):621-5.

10. Xu L, Li Y, Lang J, Xia P, Zhao X, Wang L, Yu Y, Chen L. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis. Palazón-Bru A, ed. PeerJ. 2017;5:e3405.

11. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin. Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015 Nov 26;373(22):2117-28.

12. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017 Aug 17;377(7):644-657.

13. Cavender MA, Norhammar A, Birkeland KI, Jørgensen M, Wilding JPH, Khunti K, Fu AZ, Bodegard J, Blak BT, Wittbrodt ET, Thuresson M, Hammar N, Kosiborod MN. Hospitalization for Heart Failure and Death in New Users of SGLT2 Inhibitors in Patients With and Without Cardiovascular Disease-CVD-REAL Study. Presented at: American Diabetes Association 77th Scientific Sessions; June 9-13, 2017; San Diego.

14. Wakisaka M, Nagao T. Glycobiology. Sodium glucose cotransporter 2 in mesangial cells and retinal pericytes and its implications for diabetic nephropathy and retinopathy. Glycobiology. 2017 May 23. doi: 10.1093/glycob/cwx047. [Epub ahead of print]

15. Ott C, Jumar A, Striepe K, Friedrich S, Karg MV, Bramlage P, Schmieder RE. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovascular Diabetology. 2017 Feb 23;16(1):26.

16. Chamarthi B, Ezrokhi M, Rutty D, Cincotta AH. Impact of bromocriptine-QR therapy on cardiovascular outcomes in type 2 diabetes mellitus subjects on metformin. Postgrad Med. 2016 Nov;128(8):761-769.

17. American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2012. Diabetes Care. 2013 Apr;36(4):1033-1046.

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